1) Field of the Invention
This invention relates to a sterilized cyanoacrylate adhesive composition, and to a method of making such a composition. The composition is suitable for bonding a wide range of substrates but is especially intended for medical and/or veterinary uses such as wound closure and general surgical applications.
2) Description of the Related Art
There is considerable experience in the use of cyanoacrylate adhesives in medical and veterinary practice (Shantha et al. "Developments and Applications of Cyanoacrylate Adhesives", J. Adhesion Sci. Technol Vol. 3, No. 4, pp 237-260 (1989)). Cyanoacrylate adhesives have been proposed for surgical treatment such as wound adhesives, hemostatics and tissue adhesives, particularly for sutureless skin bonding. It is desirable that an adhesive for medical or veterinary use should be sterilizable (Al-Khawan et al. "Cyanoacrylate adhesives of potential medical use", Adhesion 7 (Allen K. W.) Applied Science Publishers, Chap. 6, 109-133 (1983).
Cyanoacrylate adhesives must be stabilized against anionic and free radical polymerization. WO 8100701 Krall describes a methyl cyanoacrylate adhesive composition for sealing fallopian tubes in female sterilization containing a polymerisation inhibitor such as an organic carboxylic acid, SO.sub.2 and an antioxidant selected from hydroquinone, hydroquinone mono-methyl ether, butylated hydroxyanisole and their mixtures.
A cyanoacrylate adhesive composition for medical use is commercially available under the Trade Mark HISTOACRYL BLUE from B. Braun Melsungen AG. This composition is not sterilized.
Several methods which are available for positively sterilising liquids could be considered for application to cyanoacrylate adhesives. These include ionising radiation (electron accelerators or gamma radiation from a radioactive source such as Cobalt 60 or Caesium 137), dry-heat, steam, gas, filtration and liquid sterilisation. Aseptic filling of the adhesive immediately following manufacture is also an option. Factors to consider in choosing a sterilisation method include (a) the reactive nature of cyanoacrylates, (b) contamination due to induced chemical changes in the adhesive composition, (c) subsequent storage stability, (d) effect on bonding performance (immediate and long-term), (e) viscosity changes, (f) effect on the package or vessel used to contain the adhesive and (g) the maintenance of sterility on storage up to the time of utilisation.
Most of the above sterilisation methods are unsuitable or suffer from severe limitations in their applicability to cyanoacrylate adhesives. Electron beam accelerators have relatively low penetrating ability and would be effective only in sterilising the outer surfaces of thee container or package. Dry-heat sterilisation generally involves a heating cycle at 160.degree.-170.degree. C. for 22 hours. This treatment would be extremely detrimental to cyanoacrylate adhesives with the strong likelihood that polymerisation would occur before the cycle was complete. Even if the adhesive survived (e.g. by incorporation of excessive levels of stabilizers) the treated product would have an adverse effect on performance and induce gross discoloration. Steam sterilisation using moist heat also involves exposure to an undesirably high temperature cycle (121.degree.-141.degree. C.) with the same adverse effects on the adhesive as mentioned above under the dry-heat process. In addition, the extreme sensitivity of cyanoacrylate adhesives to moisture would limit the adhesive container to a totally moisture impermeable package such as a sealed glass ampoule. Gas sterilisation usually involves the use of ethylene oxide. While this process can be carried out at relatively low temperatures the reactivity of the gas combined with that of the cyanoacrylate adhesives would induce rapid polymerisation and make the treatment unworkable. Sterilisation by filtration is not a viable method for cyanoacrylate adhesives because the pores of the filter will inevitably become blocked due to localised polymerisation. Likewise sterilisation by contact with a liquid such as formalin will only be effective on the outer surface of the container.
Aseptic filling of the adhesive direct from the final receiving vessel used in the distillation stage of manufacture would in theory yield a sterile product. This follows because the cyanoacrylate prepolymer is cracked at temperatures of over 190.degree. C. in a sealed vessel during manufacture. The composition of the final adhesive would be very limited however, as necessary additives such as stabilizers could not be conveniently added and mixed in a controlled fashion. If required, viscosity modifiers such as polymethylmethacrylate would require heating in a separate vessel to achieve dissolution and this step would destroy the sterility.
Following on the unsuitable nature of the sterilisation methods discussed above it was decided to investigate the viability of using gamma irradiation from a Cobalt 60 source as an effective method of sterilising cyanoacrylate adhesives.
The gamma radiation emitted from a cobalt 60 source consists of high energy photons which have the ability to penetrate many materials including various plastics, liquids and metal foils. Any living microorganisms contaminating the product are deactivated and their metabolism and reproductive capabilities destroyed when they are exposed to a gamma radiation dose of 25 kGy. (Henon Y., "Gamma Processing, The State of the Art" in Medical Device Technology, June/July 1992, pages 30-37).
GB 1 281 457 (DE-OLS-2 055 658) Stehlik dating from November 1970 describes a process for irradiating monomeric or oligomeric esters of -cyanoacrylic acid for the purpose of sterlization of tissue binding adhesives. The monomers or oligomers may be stablized with from 0.001 to 0.14 by weight of a gaseous Lewis acid inhibitor, acids such as sulphur dioxide, nitrogen oxide, boron trifluoride and hydrogen fluoride, and with from 0.1 to 0.54 by weight of a phenolic free radical polymerisation inhibitor, preferably with a mixture of sulphur dioxide and hydroquinone. The patent states that as the monomeric or oligomeric compounds polymerise very readily, normal sterilisation processes including ionising radiation at room temperature are completely useless. The patent also teaches that sterilization by ionising radiation of the adhesive composition in liquid form deleteriously affects the properties of the adhesive to the extent that it becomes unuseable. The patent states that only when solid adhesive material is irradiated is it possible to prevent damage to the substance both as regards its surgical usefulness and its adhesive properties as well as viscosity and stability; the patentees therefore prefer to cool the monomeric or oligomeric compounds to a temperature of not more than -30.degree. C. The three working examples in the patent are carried out at -196.degree. C., -80.degree. C. and -183.degree. C. respectively. No stabilizers are used in any of the working examples. Example 1 states that an adhesive substance which was exposed to 0.2 Mrad (2 kGy) gamma-ray dose at room temperature polymerised completely.
To carry out irradiation at low enough temperatures to achieve solidification of the adhesive composition is not a practical proposition for industrial production. Sterilization should be performed on the liquid adhesive temperature at or near to room temperature.
A minimum dose requirement of 25 kGy (2.5 Mrad) gamma radiation is generally accepted as adequate for the purpose of sterilization (U.K. Department of Health "Quality Systems for Sterile Medical Devices and Surgical Products", 1990 Good Manufacturing Practice, HMSO, London). A dose of 2 kGy (0.2 Mrad) would be wholly inadequate for achieving sterilization.
U.S. Pat. No. 3,527,224 Rabinowitz describes a method of surgically bonding tissue using an adhesive composition based on n-pentyl alpha-cyanoacrylate which is subjected to partial polymerisation to increase its viscosity. Radiation such as gamma rays can be used to get both the desired partial polymerisation and sterilization in a one-step process. However a free-radical inhibitor must be introduced into the composition after the irradiation, with the risk of introducing bacterial contamination. The method of thickening would be difficult to quench effectively after the desired viscosity is achieved.
The present Applicants have invented a sterilized adhesive composition which contains monomeric cyanoacrylate in a substantially ungelled condition and which therefore is of low viscosity. The composition contains all of the necessary ingredients before it is sterilized by irradiation. The composition can be readily and fully sterilized by gamma irradiation with a minimum dose of 25 kGy (2.5 Mrad) at room temperature without any significant increase in viscosity while mantaining the necessary performance and shelf-life of the adhesive.
Hydroquinone is generally used as the free-radical stabilizer for cyanoacrylate adhesives under normal ageing conditions. If a sufficient concentration (e.g. 500-1000 ppm) is present it will also be an effective stabilizer to prevent polymerisation during gamma irradiation treatments. However chemical changes to the hydroquinone molecule occur during the treatment, resulting in the conversion of approximately 25% of the hydroquinone to 1,4-benzoquinone. This material is known to be toxic and its presence in an adhesive, especially if used for medical applications, would be undesirable.
It is an object of the present invention to provide a sterilized cyanoacrylate composition which does not have the disadvantages discussed above.
It is a particular object of the invention to provide a sterilized cyanoacrylate composition which is substantially free of toxic contaminants, especially 1,4-benzoquinone.